3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, also known as tetrabenazine (TBZ), has been used as a drug for decades. Tetrabenazine is a potent, reversible inhibitor of catecholamine uptake by vesicular monoamine transporter-2 (VMAT2) (IC50=3.2 nM) (Scherman, et al, Proc. Natl. Acad. Sci. USA, (1983) 80:584-8) and is currently used in the treatment of various hyperkinetic movement disorders. Side effects associated with TBZ include sedation, depression, akathisia, and parkinsonism. Inhibition of VMAT2 by TBZ results in depletion of brain monoamines in vivo (Pettibone, D. J. et al., Eur. J. Pharmacol. (1984) 102:431-6). TBZ also inhibits presynaptic and postsynaptic dopamine receptors in rat brain (Login, I. S., et al., (1982) Ann. Neurology 12:257-62; Reches, et al, J. Pharmacol. Exp. Ther. (1983) 225:515-521). This off-target activity of TBZ may be responsible for some of the observed side effects.
TBZ, which contains two chiral centers and is a racemic mix of two stereoisomers, is rapidly and extensively metabolized in vivo to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known as dihydrotetrabenazine (HTBZ). HTBZ is thought to exist as four individual isomers: (±) alpha-HTBZ and (±) beta-HTBZ. The 2R, 3R, 11bR or (+) alpha-HTBZ is believed to be the absolute configuration of the active metabolite (Chirality 1997 9:59-62). Despite its success in treating hyperkinetic disorders, tetrabenazine has a fairly low and variable bioavailability. Tetrabenazine administration to humans is complicated by extensive first pass metabolism and little or no tetrabenazine is observed in the urine.
There is a need in the art for analogs of tetrabenazine that provide the advantageous properties of tetrabenazine without exposing the body to all of stereoisomers of dihydrotetrabenazine. There is also a need for analogs of tetrabenazine that exhibit a longer half-life than tetrabenazine. There is likewise a need in the art for analogs of tetrabenazine that exhibit greater selectivity for VMAT2 than tetrabenazine. The present invention provides a tetrabenazine analog that exposes the body to a single stereoisomer of dihydrotetrabenazine, exhibits greater selectivity for VMAT2 than tetrabenazine, exhibits a longer half-life than tetrabenazine, and may exhibit lower variability in dose required from patient to patient.